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using a similar protocol, XPA-deficient mice only developed papillomas (10, and
this study).
DISCUSSION
Since the identification of CS and TID as DNA repair disorders, the paradoxical
absence of skin cancer predisposition in these NER -deficient patients has been
puzzling. The set of NER-deficient mice generated in our, and collaborating
laboratories allows a quantitative and in vivo approach towards elucidating the role
of DNA damage and repair in the multi-step process of carcinogenesis. This paper
describes cellular repair parameters, quantitation of UV -induced inflammation of
the skin and carcinogenic properties of TTD mice compared to other NER-deficient
mouse mutants. In contrast to the human syndrome, TID mice arc clearly
predisposed to develop skin cancer although not as cancerprone as XPA mice.
Repair defect in TTD mice
The TTD-specific XPD R7 :!:!1V allele, which we mimicked in the mouse genome, is
associated with a clear but partial DNA repair defect in human fibroblasts. RNA
synthesis recovery was severely but not completely abolished (Table 1). Moreover
UDS, UV-induced mutagenicity levels in a plasmid-based study (22) and UV-
Table II DMBA-induced tumorigenesis in TTD, wild-type and XPA-deficient mice
Papilloma d
Squamous cell carcinoma
XPA" 100% n.d. c
TTO b
40 % (IS) 60 % (2S)
wild-type 10%(1) 90 % (9)
.1(10); b This study. < Not detected. d Number of tumors between brackets.
survival employing a protocol with non-cycling cells were comparable between
TTD/XPD R722W fibroblasts and fibroblasts from XP patients of complementation
group D (4, 29).
Despite the repair defect, TID mouse skin appears not very sensitive to either UVinduced
inflammation (only slightly more sensitive than wild-type mice do) or
hyperplasia induced by UV or DMBA. In TTD patients, photosensitivity of the skin
has been reported, but ethics constrain experimental quantitation of this symptom.
In addition, mild pigmentation abnormalities upon sunlight exposure, one of the
hallmark features of XP, have been reported sporadically in TID patients (4, 16),
suggesting that the TTD repair defect resembles XP in this respect, albeit to a mild
extent. In vivo, photosensitivity in TTD mice and patients may be moderated by
UV-shielding by the thick hyperkeratotic epidermis. However, also the eyes ofTTD
TID mice reveal cancer-predisposition 95